Alzheimer's disease (AD) is characterized by the presence of senile plaques composed primarily of deposits of the beta-amyloid protein (A- beta). A-beta is an about 4 kD peptide derived from larger amyloid precursor proteins (APP). We used low-stringency hybridization to identify mouse cDNA that encode APLP2, a member of APP gene family. APLP2 is highly homologous to mouse APP-751 within the Kunitz protease inhibitor domain, the N-terminal cysteine-rich region, and the cytoplasmic domains. APLP2 mRNA is expressed at significant levels in the brain and peripheral tissues of mouse. In vitro studies in cell-free translation systems and transfected cells reveal that APLP2 matures through the secretory pathway. Similarities in constitutive maturation of APP and APLP2 strongly suggest that enzymes with overlapping specificities may be involved in posttranslational modification of these polypeptides. Furthermore, our demonstration, by in situ hybridization, that APLP2 and APP mRNA are expressed in similar neuronal subsets in mouse grain suggests that APLP2 and APP expression may be controlled by similar genetic elements. We propose to address two issues that relate APLP2 expression. The first series of experiments are designed to examine whether APLP2 can compete with enzymes used for APP maturation to assess whether these proteins utilize identical pathways. In these studies, we will compare the maturation of APP in cells transfected with APP cDNA alone or in cells cotransfected with APP and APLP2 cDNA. In parallel, we will use epitope tags in coimmunoprecipitation studies to assess whether APP and APLP2 interact physically following expression in transfected cells. Secondly, we will isolate the APLP2 promoter and characterize its expression in transfected cells, using reported gene strategies. The promoter fragment will then be used in conjunction with a Lac Z reporter to examine the expression of the APLP2 promoter during development in transgenic mice. The possible influence of APLP on the biology of APP are not known; these studies represent a first step in the new and important area of research.